Pro-inflammatory cytokines and chemokines initiate multiple prostate cancer biologic pathways of cellular proliferation,heterogeneity and metastasis in a racially diverse population and underlie the genetic/biologic mechanism of racial disparity: Update

Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article.Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue.Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens.Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow.Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy.     

Anterior urethral valve in an adolescent boy

A 14 year old boy with a relatively uncommon anterior urethral valve is described herein.     

Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.     

Synthesis and biological studies of triazolo-/thiadiazolo-benzoxazines

Diethyl bromomalonate (2) with an equimolar amount of 2-aminophenol (1) in the presence of sodium fluoride undergoes a cyclization reaction to form 2H,4H-2-ethoxycarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (3). Furthermore, compound 3 undergoes a condensation reaction with hydrazine hydrate in the presence of methanol to yield 2H,4H-2-hydrazinocarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (4), which on further reaction with aryl isothiocyanates gave 2H,4H-2-[ (4'-substituted)-phenylthiosemicarbazino]-carbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (5). Compound 5 on treatment with NaOH, cone. H2SO4 and diethylmalonate (6). afforded 2H,4H-2-[2'H-3'-thioxo-4'-substituted phenyl-1',2',4'-triazole-5-yl]- 3,4-dihydro-3-oxo-1,4benzoxazine (7). 2H,4H-2-[2'-amino-(substituted)-phenyl-1,3',4'-thiadiazol-5-yl]-3,4-dihydro-3-oxo-1,4-benzoxazine (8) and 2H,4H-2-[5'H-5'-dihydro-2'-thioxo-3'-phenyl-4',6'-dioxo-1,3-diazine]-aminocarbonyl-3,4-dihydro-3-oxo-1,4-benzoxazine (9), respectively. The synthesized compounds were investigated for their antibacterial activities against Gram positive as well as Gram negative bacteria with ampicillin trihydrate as standard drug. Structures have been elucidated on the basis of spectral and chemical analyses.     

2'-Methoxy-6-methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA(A) receptors

BACKGROUND AND PURPOSE

Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.

EXPERIMENTAL APPROACH

We evaluated the effects of 2′-methoxy-6-methylflavone (2′MeO6MF) on native GABA_A receptors in new-born rat hippocampal neurons and determined specificity from 18 human recombinant GABA_A receptor subtypes expressed in Xenopus oocytes. We used ligand binding, two-electrode voltage clamp and patch clamp studies together with behavioural studies.

KEY RESULTS

2′MeO6MF potentiated GABA at α2β1γ2L and all α1-containing GABA_A receptor subtypes. At α2β2/3γ2L GABA_A receptors, however, 2′MeO6MF directly activated the receptors without potentiating GABA. This activation was attenuated by bicuculline and gabazine but not flumazenil indicating a novel site. Mutation studies showed position 265 in the β1/2 subunit was key to whether 2′MeO6MF was an activator or a potentiator. In hippocampal neurons, 2′MeO6MF directly activated single-channel currents that showed the hallmarks of GABA_A Cl^- currents. In the continued presence of 2′MeO6MF the single-channel conductance increased and these high conductance channels were disrupted by the γ2(381–403) MA peptide, indicating that such currents are mediated by α2/γ2-containing GABA_A receptors. In mice, 2′MeO6MF (1–100 mg·kg⁻¹; i.p.) displayed anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark tests. 2′MeO6MF induced sedative effects at higher doses in the holeboard, actimeter and barbiturate-induced sleep time tests. No myorelaxant effects were observed in the horizontal wire test.

CONCLUSIONS AND IMPLICATIONS

2′MeO6MF will serve as a tool to study the complex nature of the activation and modulation of GABA_A receptor subtypes.     

Design,Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors

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Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design,Synthesis, and Pharmacology

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Alpha blocker prazosin for the treatment of benign prostatic hypertrophy (BPH)

In this study medical treatment with alpha blocker-prazosin is compared with transurethral resection of prostate (TURP) in 62 patients suffering from benign enlargement of prostate with a gland size of less than 20 gms. After thorough interrogation patients were offered either TURP or prazosin therapy. Symptom scoring, residual volume of urine and urinary flow rates were estimated in both the groups before and 3 months after the therapy. 23.5% patients in prazosin group while 90% of patients in TURP group had significant improvement. This distinctly brings out the superiority of TURP for benign enlargement of prostate.     

Solar energy as a renewable energy source for preparative-scale as well as solvent and catalyst-free Hantzsch reaction

A well-known Hantzsch reaction for the synthesis of 1,4-dihydropyridine was performed in an eco-friendly manner using concentrated solar radiation. Solvent and catalyst-free approach with excellent yield is the key feature. The present mild, green, and energy-efficient method tolerates the various substrates. Multi-gram scale up (50 mmol), shorter reaction time, simple work-up procedure and high atom efficiency are the added advantages of this reported protocol.     

3-Hydroxy-2'-methoxy-6-methylflavone: a potent anxiolytic with a unique selectivity profile at GABA(A) receptor subtypes

Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA_A receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA_A receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2′-methoxy-6-methylflavone (3-OH-2′MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1–3γ2L but not α3/5β1–3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC₅₀ values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2′MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4–11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2′MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2′MeO6MF for α4β2/3δ receptors (EC₅₀ values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA_A receptors. 3-OH-2′MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2′MeO6MF (1–100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2′MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA_A receptor subtypes.